The present invention relates to the prevention of sepsis and the treatment of systemic inflammatory response syndrome. More specifically, the present invention relates to the prophylactic use of a hemoglobin preparation to reduce the severity of, or to prevent, sepsis in patients recognized to be at risk for developing sepsis. The invention also relates to the therapeutic use of a hemoglobin preparation to treat systemic inflammatory response syndrome in patients diagnosed as suffering from systemic inflammatory response syndrome.
A systemic inflammatory response can be observed after a patient suffers an infectious or noninfectious insult. If the inflammatory response results from a noninfectious cause, the response is generally known as systemic inflammatory response syndrome. A frequent complication of the syndrome is organ dysfunction. Inflammatory responses resulting from infection are generally defined as sepsis (ACCP/SCCM (1992), Critical Care Medicine, 20(5):864-874).
Sepsis results from acute invasion of the bloodstream or other tissues by pathogenic microorganisms or toxic products thereof, such as bacterial endotoxins. Sepsis is often caused by infection with bacteria, pathogenic viruses, fungi, or protozoa. Sepsis resulting from infection can be clinically diagnosed by positive blood cultures. Additional clinical evidence suggestive of infection or a systemic response to infection is evident as sepsis progresses. This clinical evidence includes tachypnea, tachycardia, and hyperthermia or hypothermia, followed by abnormal lactate levels, oliguria, obtundation and other signs of altered organ perfusion normally associated with incipient septic shock. Early stage septic shock is manifested by hypotension that lasts for less than one hour and which is responsive to conventional therapy such as intravenous fluid administration or pharmacologic intervention. Refractory septic shock can be diagnosed by hypotension that lasts for more than one hour despite adequate volume resuscitation and that requires the use of vasopressors or higher doses of dopamine (Bone (1991) Ann. Int. Med. 115:457-469). Multiorgan failure can occur as or after a patient suffers septic shock.
Sepsis and subsequent multiple system organ failure (MSOF) are a major cause of late morbidity and mortality in trauma victims (Carrico et al. (1986) Arch. Surg. 121:196-208; Goris et al. (1985) Arch. Surg. 120:1109-1115; Fine et al. (1959) N. Engl. J. Med. 260:214-220; Rush (1989) Ann. Surg. 210:342-347). In more than 30% of bacteremic trauma patients dying of sepsis and its sequelae, no focus of infection can be identified either clinically or at autopsy. While clinical studies have so far failed to establish a cause and effect relationship between gut failure and systemic sepsis or MSOF, the infection of these patients with bacteria normally found within the gastrointestinal tract has led many clinicians and scientists to hypothesize that these infections originated in the gut (Deitch (1990) Arch. Surg. 125:403-404; Livingston (1993) Am. J. Surg. 165:8S-13S; Sori et al. (1988) Am. J. Surg. 155:187-192; Wilmore et al. (1988) Surgery 104:917-923; Zhi-Yong et al. (1992) J. Trauma 32:148-153).
Hemoglobin has been administered to increase perfusion, and increase blood pressure from abnormally low levels, in patients experiencing septic shock (U.S. Pat. No. 5,334,706), to protect against endotoxic shock when administered to rats at a concentration of 300 mg/kg body weight before inducing endotoxic shock (Otterbein et al. (1995) Amer. J. Resp. Cell Mol. Bio. 13:595-601), and for prophylaxis or treatment of septic shock induced by internal nitric oxide production at a hemoglobin concentration of 100-10,000 mg/kg body weight (U.S. Pat. No. 5,296,466).
Current experimental approaches to treating septic shock employ monoclonal antibodies against endotoxin components and TNF, and the use of platelet-activating factor antagonists (Stone (1994) Science 264:365-367). Mortality due to septic shock varies from 20 to 60% despite the use of antibiotics and intensive supportive care (Bone et al. (1987) N. Engl. J. Med. 317:653-658; Kreger et al. (1980) Am. J. Med. 68:344-355; The Veterans Administration Systemic Sepsis Cooperative Study Group (1987) N. Engl. J. Med. 317:659-665).
A need therefore exists for agents effective in preventing or reducing the severity of sepsis in mammals. Agents for treating systemic inflammatory response syndrome in mammals are also needed.